The human immunodeficiency virus (HIV) was first identified as the causative agent of acquired immunodeficiency syndrome (AIDS) in 1983.1 At the close of 2010 there were an estimated 34 million people living with the retrovirus worldwide, with approximately 2.7 million people newly infected in 2009 alone.2 The introduction of the drug regimen HAART (highly active antiretroviral therapy) in 1996 has transformed HIV from a lethal infection to a manageable chronic condition with considerable declines in HIV-associated morbidity and mortality.3-8 However, as a result of the high genetic variability of the retrovirus, resistance to current drug therapies is a major problem and in addition to HIV there are numerous other chronic viral infections such as hepatitis B and C and human T-lymphotrophic virus 1 (HTLV-1).7 Approximately 1 in 12 persons worldwide, or some 500 million people, are living with chronic viral hepatitis.2 In light of this, a vast amount of time and effort has been invested in the design and synthesis of antiviral agents, most notably nucleoside analogues and the discovery of new, more efficient antiviral agents is imperative.
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of anti-HIV drugs approved and, despite the discovery of numerous other classes of anti-HIV agents (i.e. nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, cell entry inhibitors and co-receptor inhibitors), they have continued to play a pivotal role in HIV treatment.8 NRTIs disrupt viral replication through two distinct modes; competitive inhibition of HIV RT with respect to the dNTP substrate, and DNA chain termination.9,10 However, in order to do this, these compounds must be first converted via a series of host cell kinases to their active triphosphate form.10-12 The triphosphorylated drug molecules then compete with bona fide nucleotides to be accepted into the growing DNA chain and, if incorporated, chain elongation is terminated since the NRTI lacks the 3′-OH group of endogenous nucleosides.10 Poor cell membrane permeability coupled with the labile nature of the phosphate bond precludes the direct delivery of the active triphosphorylated form of the drug into the virus-infected cell.13 This predicament was partially overcome by the use of phosphoramidate, CycloSal or alkoxyalkyl prodrug technologyl4-17 and also the discovery of the phosphonate as a stable isostere for the phosphate bond.18,19 
The discovery of (S)-HPMPA as a broad spectrum antiviral agent swiftly led to the development of a new class of antiviral agents; the nucleotide reverse transcriptase inhibitors (NtRTIs).19,20 Tenofovir (PMPA) is the only nucleotide reverse transcriptase inhibitor currently approved by the FDA for the treatment of HIV and HBV. It is marketed as the prodrug tenofovir disoproxil fumarate (TDF) which is hydrolysed in vivo to tenofovir.8,10 The presence of the phosphonate group enables the compound to bypass the initial phosphorylation, which is often the rate-limiting step, and just two phosphorylations are required to furnish the active tenofivir-diphosphate.8 
Carbocyclic nucleosides are an important subclass of NRTIs where the oxygen of the furanose ring has been replaced by a methylene group.21-23 This substitution renders these compounds stable to cleavage by intracellular phosphorylases and hydrolases as they lack the labile glycosidic bond of natural nucleosides. Carbocyclic nucleosides also exhibit increased lipophilicity relative to conventional nucleosides leading to increased in vivo half-life, oral efficiency and cell membrane penetration.22 Naturally-occuring compounds of this type include aristeromycin 1 and neplanocin A 224 which possess potent antitumor and antiviral activities. Synthetic carbocyclic derivatives include the antiviral agents abacavir 325 and carbocyclic-ddA 4.26

The phosphononucleoside 527 and the carbocyclic phosphononucleoside 628 possess significant anti-HIV activity. The diphosphorylated carbocyclic phosphononucleoside derivative 7 also strongly inhibits HIV-RT.18 In addition to this, the antiviral properties of phosphonoformic acid (PFA) 8 and phosphonoacetic acid (PAA) 9 were established almost 3 decades ago.29 McKenna et al. later synthesised a range of halogen- and methyl-substituted derivatives of PAA, a number of which were found to possess potent antiviral activity. Interestingly, the carbonyl derivative 10 was significantly more active than 9.30

In general, phosphononucleoside research involves compounds bearing a simple CH2PO(OH)2 substituent; however, there have been some reports of derivatives bearing substituents geminal to the phosphonic acid moiety.31-36 Gilbert and co-workers described the synthesis of citrate derivatives of nucleosides as potential mimics of nucleoside triphosphates.37,38 The compounds were found to be inactive, indicating that the citrate moiety is not a good replacement for the phosphate group. Vedras et al. reported the synthesis of nucleoside dicarboxylates as potential nucleoside diphosphate isosteres.39 Recently Janeba has described acyclic nucleoside phosphonates incorporating an additional remote carboxylic acid function, but these compounds did not exhibit any antiviral activity.40 The attachment of PAA and PFA by ester and amide linkages to the 5′-O and N-positions of 3TC has been reported previously, but the resulting derivatives were less active against HIV-1 than the parent compound.41 
The present invention seeks to provide further phosphononucleoside derivatives, particularly those that have therapeutic applications in the treatment of viral disorders, including DNA and RNA viruses such as HIV.